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Pre-existing antibodies to endemic coronaviruses (CoV) that cross-react with SARS-CoV-2 have the potential to influence the antibody response to COVID-19 vaccination and infection for better or worse. In this observational study of mucosal and systemic humoral immunity in acutely infected, convalescent, and vaccinated subjects, we tested for cross reactivity against endemic CoV spike (S) protein at subdomain resolution. Elevated responses, particularly to the β-CoV OC43, were observed in all natural infection cohorts tested and were correlated with the response to SARS-CoV-2. The kinetics of this response and isotypes involved suggest that infection boosts preexisting antibody lineages raised against prior endemic CoV exposure that cross react. While further research is needed to discern whether this recalled response is desirable or detrimental, the boosted antibodies principally targeted the better conserved S2 subdomain of the viral spike and were not associated with neutralization activity. In contrast, vaccination with a stabilized spike mRNA vaccine did not robustly boost cross-reactive antibodies, suggesting differing antigenicity and immunogenicity. In sum, this study provides evidence that antibodies targeting endemic CoV are robustly boosted in response to SARS-CoV-2 infection but not to vaccination with stabilized S, and that depending on conformation or other factors, the S2 subdomain of the spike protein triggers a rapidly recalled, IgG-dominated response that lacks neutralization activity.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This work was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, as well as extramural support from the National Institute of Allergy and Infectious Diseases (U19AI145825 to M.E.A, R01AI120938, R01AI120938S1, and R01AI128779 to A.A.R.T.), National Heart Lung and Blood Institute (K23HL151826 to E.M.B.), National Institute of General Medical Sciences (P20-GM113132 BioMT Molecular Tools Core).

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Human subject research was approved by the Johns Hopkins University School of Medicine Institutional Review Board and the Dartmouth-Hitchcock Medical Center and CHU St. Pierre and Hadassah Medical Center and BioIVT clinical site Committees for the Protection of Human Subjects

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Paper in collection COVID-19 SARS-CoV-2 preprints from medRxiv and bioRxiv

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